Angiogenesis is the process of inducing new blood vessels. Angiogenesis-producing factors are signals that serve as stimuli to cause angiogenesis. The result of angiogenesis is neovascularization to initiate a blood supply to a tissue or to revascularize ischemic tissue. Neovascularization or revascularization by angiogenesis-producing factors includes recanalization whereby hollow capillary tubes form to support a blood supply.
Angiogenesis is also the process whereby a tissue responds to a tumor by inciting growth of new blood vessels toward the tumor. Beside tumors, substances that may induce angiogenesis include proteolytic enzymes, growth factors, and chemicals such as EDTA.
Proteolytic enzymes are secreted by tumor cells or destroyed cells in the process of cytolysis. These enzymes induce cell movement toward their chemical stimuli in the process of chemokinesis. Chemicals such as EDTA can cause instability of a cell membrane and similarly trigger cell movement. It has been also shown that growth factors, such as fibroblast growth factor (FGF), transforming growth factor (TGF), nerve growth factor (NGF), and so on, play a role in regulating proliferation of endothelial cells. Regardless of the pathogenesis of angiogenesis, the process is accompanied by proliferation of endothelial cells from initially normal vessels toward the stimulus.
Folkman in 1971 proposed the concept of anti-angiogenesis. Anti-angiogenesis involves inhibiting new blood vessel formation in order to either prevent growth of a tumor or control growth of metastatic tumors. Much work has been done in this area to identify and test anti-angiogenesis agents. Examples of such agents include anti-inflammatory or suppressive factors (inhibitors) that prevent endothelial cell proliferation, and inhibitors of proteolytic enzymes such as plasminogen activator inhibitors. Such inhibitors can prevent the breakdown of the protein matrix and maintain the integrity of endothelial cells, thereby preventing their migration. Efforts in this area have been concentrated in attempting to treat tumors by preventing neovascularization.
Although in the last two decades there have been attempts to revascularize an ischemic area of myocardial tissue using laser energy, these attempts have been only partially successful. This is due to laser-induced channels closing by themselves, as well as to the unpredictable rate of revascularization of these channels. Similarly, in central retinal vein thrombosis, attempts have been made to rupture small retinal veins with laser energy applied in a transpupillary direction, thus also rupturing Bruch""s membrane in the hope of creating a channel from the retina to the choroidal circulation. These techniques have met with only minimal success; less than a 30% success rate has been achieved with this method to create new channels. Additionally, revascularization of the retina cannot occur in patients who have central vein occlusion or other diseases which create capillary occlusion in the retina or any other organ, such as the brain.
The present invention is directed to a method and device for treating anoxic tissue. A physiologically compatible device supports an angiogenesis factor in an amount for treating an anoxic tissue. The device is implanted in the anoxic tissue so as to induce revascularization of the tissue.
The invention is also directed to a method of making an angiogenesis-inducing implant, comprising supporting an angiogenesis factor on a physiologically compatible substrate for retaining the factor, to form an implantable device.
The invention also describes methods and materials used to successfully induce neovascularization in an ischemic tissue, in an attempt to reestablish function of these tissues. In particular embodiments, the devices and methods of the invention may be used to revascularize anoxic heart and eye tissue.
Until now, no attempt has been made to in fact use angiogenesis-stimulating factors to revascularize ischemic tissue. One example where angiogenesis-stimulating factors may be used is in a damaged heart muscle where closure of one or more coronary arteries has resulted in a myocardial infarction. Such closure leads to either acute myocardial infarction or to a gradual cardiomyopathy, with its predominant symptom of angina pectoris. Another example where angiogenesis-stimulating factors may be used is in anoxic tissue in the eye. Central retinal artery occlusion in the eye causes immediate discontinuation of blood supply to the retina. If this condition is not treated within a short period of time, or if the vessels are not reopened by themselves, pushing microemboli in the peripheral branches, complete loss of sight occurs. Another example is central vein occlusion that results from thrombosis of the central retinal vein. Lack of blood flow in the central retinal vein produces congestion, with subsequent breakdown of the capillary network and hemorrhage in the retinal tissue. Lack of oxygen and nutrients, carried by blood, produces ischemic processes in the retina and may result in the loss of sight.
Other advantages and embodiments will be understood with reference to the drawings and following detailed description.